The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), the NIH
Office of Rare Diseases (ORD), and the Tourette Syndrome Association (TSA) jointly sponsored a workshop to develop new and
improved treatments for children and adults afflicted with Tourette syndrome (TS). The workshop was held on September 10-12,
2006, and included approximately 100 scientists, clinicians, and industry representatives in the fields of basic neurobiology,
behavioral sciences, neurogenetics, neuroimaging, neurological disorders, motor disorders, and child psychiatry. The attendees
from within and outside the TS field convened with the express purpose of bridging the communication and information gap between
basic and clinical science disciplines to evaluate the biological and clinical basis for existing TS treatments and to understand
recent updates in the neurobiology of TS in order to define new therapeutic directions.

The meeting began with an overview of the phenomenology of TS and existing treatments. TS is characterized by an enduring
pattern of motor and phonic tics that present during childhood. According to current best estimates, TS affects approximately
6 of every 1000 schoolchildren. The severity and frequency of tics peak early during the second decade of life, but then decline
considerably in many patients by their late teens and early 20s. Currently, there is no curative pharmacological treatment
for TS, but several agents have proven successful at attenuating tics and improving psychosocial functioning. Since TS is
associated with improper dopaminergic tone in the brain, atypical neuroleptics (e.g., risperidone) and typical neuroleptics
(e.g., haloperidol) that function by blocking dopamine signaling at D2 receptors are commonly prescribed. Other commonly used
agents include 2-adrenergic agonists (e.g., clonidine). Botulinum toxin A is increasingly being used to treat severe focal
tics. In terms of behavioral approaches for tic control, habit reversal training, which employs competing responses to block
tic manifestation, has been shown to be an effective technique in adults and appears to also work in children. A handful of
case studies suggest that deep brain stimulation, in which electrodes are implanted into specific brain regions to deliver
electrical pulses to prevent tics, is a promising approach for controlling TS, but considerably more study of the technique
is needed.

The next portion of the workshop centered around presentations highlighting the brain structures and neural circuitry implicated
in TS. Research indicates that TS is very likely caused by abnormal signaling between various circuits in the brain that manifests
during development. The chief circuit involves the cerebral cortex, basal ganglia, and thalamocortical regions, with the basal
ganglia being a key node in the circuit. Dopamine signaling within the basal ganglia serves to define the salience of information
by filtering out "inappropriate" behaviors. Like others, individuals with TS are constantly bombarded with stimuli at the
site of the basal ganglia; however, this region of the brain is impaired in its ability to discriminate between salient and
nonsalient signals. Importantly, it appears that the ventral striatum is the primary locus of dysfunction within the basal
ganglia in TS individuals. Although the cause of basal ganglia dysfunction is not well understood, clues may be found by examining
the structure of TS brains. A comparison of postmortem basal ganglia tissue from patients with severe TS and normal controls
indicates a below-normal density of inhibitory neurons in the striatum and an above-normal density in the internal segment
of the globus pallidus within the basal ganglia.

Additional information about the pathology of TS may be gleaned from studies of related neural processes and/or abnormalities.
Striatal neurons and dopamine signaling play a key role in the process of habit formation, particularly habits involving complex
and socially relevant behavioral sequences, as is observed in TS patients. Certain areas of neural convergence in the striatum
may be particularly sensitive to dopamine modulation during decision-making and habit formation - areas that may be hypersensitive
or overactive in TS. Related to habit formation is the biology of addiction, which may parallel the neurobiochemical processes
occurring in TS. Individuals with strong tics may have progressed through the process of overlearning such that they become
"addicted" to tic behavior as a means to relieve the mounting internal stress or body tension that is often described as characteristic
of TS. Addiction studies have revealed that overlearning is associated with heavy dopamine release that activates the prefrontal
cortex, which, in turn, releases a surge of glutamate on the nucleus accumbens that then drives drug seeking.

There are no animal models for TS, but syntactic chain grooming in rats is a relevant behavior to study since it is sequential,
rule driven, and predictable, yet flexible, much like tics. In addition, studies have shown that the stereotypical movement
is regulated by the ventral striatum. Interestingly, D1 agonists dramatically upregulate chain behavior, suggesting that D1
receptor antagonists may suppress this behavior. Because tics are often preceded by premonitory urges, additional insight
into the neurobiology of TS and potential therapeutics may be gained by studying prepulse inhibition in rats, which is abrogated
by increased dopamine signaling and/or disruption of the ventral striatum.

Pharmacological therapies for TS have traditionally focused on dopamine mechanisms. However, just as different areas of the
brain are implicated in TS, so too are different neurotransmitter systems that interact and overlap to contribute to the pathophysiology
of TS. Salient interactions include those between dopamine and glutamate, dopamine and serotonin, and dopamine and GABA.

Given the neurobiology underlying TS pathogenesis and the similarities between TS and other neural processes, several attractive
pharmacotherapeutic targets for TS emerged during the workshop. These include compounds targeting monoaminergic systems (e.g.,
D1 receptor antagonists, serotonin agonists or selective serotonin reuptake inhibitors), agents that regulate the prefrontal
glutamatergic drive to the nucleus accumbens (e.g., N-acetylcysteine, modafinil), and agents that reinstate GABA receptor
function or enhance GABA activity. The application of brain imaging, particularly between sibling pairs, and better identification
of the genes involved in TS (e.g., SLITRK1) will facilitate more refined therapeutic approaches.

In order to better poise the TS field to make substantial progress in translating research from the bench to the bedside,
several individuals investigating other human disorders presented their experiences with coordinating and accelerating the
therapy development process. One particular strategy that may bring TS therapeutics to the clinic relatively quickly and easily
is to identify new applications for approved drugs or drugs that went through clinical trials but failed to receive FDA approval.
Additionally, the NIH offers several resources to facilitate translational research.

In the concluding discussions, the workshop participants recognized that TS drug development is hampered by two difficulties:
(1) there is no animal model of TS for preclinical analysis, and (2) it is difficult to enroll large clinical trials to assess
a particular therapeutic. To circumvent these difficulties, it was proposed that a collaborative pilot study group be formed
to perform small experimental trials in TS patients in order to cultivate larger trials of appropriate drugs in appropriate
patients. The formation of a pilot study consortium would serve to augment the TSA International Genetics Consortium, the
TSA Behavioral Sciences Consortium, and the TSA Neuroimaging Consortium already in existence. Participants also expressed
that larger clinical trials must be thoughtfully designed to enable researchers to discern which subgroups of TS patients
(e.g., based on genetic polymorphisms, functional imaging, the type and severity of tics) derive benefit from a given therapeutic.
In addition, some proposed that other measures of improvement, aside from tics, be included in such analyses, such as improvements
in quality of life. These ideas have the opportunity to gain further momentum since the TSA is planning another meeting in
early 2007 that will focus on pragmatic approaches to clinical trial design and treatment exploration.

Background and Goals of Workshop:

Tourette Syndrome (TS) is a familial, neurological disorder defined by the childhood onset of chronic motor and vocal tics.
The tics of TS most often involve rapid, jerky movements such as blinking, facial movements, head jerking and simple vocalizations
such as throat clearing, coughing, grunting and other brief noises. In other cases, however, the tics are more complex involving
multiple muscle groups and more complex vocalizations including cursing and repetition of words or phrases. In addition to
tics, a high percentage of patients with TS have significant problems with obsessive-compulsive behaviors (OCD) as well as
inattention, hyperactivity, and impulsiveness (ADHD) or a combination of these problems. In many cases, these co-occurring
conditions when present are more impairing than the tics themselves. Although TS and associated conditions are not life-threatening,
the tics can be debilitating, painful and may cause impairment at school or work and social isolation, especially in children.
Given the current estimates of prevalence ranging from 0.1 to 1% for TS (up to 6% for transient tics), TS is a significant
public health problem.

Most pharmacological treatment trials in TS have focused on tic reduction. Antipsychotic drugs with potent dopamine blockade
at D2 receptors are the best-studied and most commonly prescribed class of medications used for tic reduction. Although available
evidence indicates that the D2 antagonists are effective for reducing tics, at least in the short-term, these agents are not
free of adverse effects, and are often discontinued because of debilitating or dangerous side effects (sedation, dyskinesias,
weight gain, cardiac arrhythmias in some people). Another commonly used class of medications is the alpha-2-norepinephrine
agonist class. However, the magnitude of effect is typically moderate with this class of drugs, and success with alternative
medications has been limited. Preliminary data are available for dopamine agonists and drugs that enhance GABA. However, few
drug treatments have been selected in accordance with contemporary understanding of putative TS pathophysiology. Recently,
converging information from neuroimaging, neuropathology, psychophysiology, genetics and behavioral neuroscience offer exciting
new opportunities for understanding the etiology of TS and for developing optimal treatments for this disorder. In addition
to pharmacological therapies, new behavioral approaches suggest novel opportunities for reducing tics and associated disability
in people with TS through non-pharmacological means as well as with combined treatments. We hope that a focused dialogue between
basic neuroscientists and clinical investigators will guide the identification and selection of candidate treatments for TS
in the near term and lead to improved strategies for therapy development in the future.

The overall goal of this conference is to develop improved treatments for children and adults with Tourette syndrome. The
conference will bring together clinical investigators, basic and translational scientists representing a range of scientific
disciplines from within outside the TS field to evaluate the evidence for existing TS treatments and the latest information
on the neurobiology that is relevant to TS in order to identify new treatments. Another goal is to adopt novel strategies
for therapy development in TS based on insights gained from translational approaches in other disease areas and from industry.
The workshop will conclude with a session on defining future directions in neuroscience and clinical research. The conference
hopes to encourage new interdisciplinary collaborations among junior and established investigators in order to guide the identification,
development and testing of new treatments for people with TS.

The conference organizers plan to disseminate the discussions and recommendations from this meeting to investigators and clinicians
working in the TS field. The published proceedings will aim to identify opportunities and new directions in translational
and clinical research in TS.